Mechanistic Modelling and Simulation in Medicines Development:

Diabetes

Maria C. Kjellsson, PhD

Pharmacometrics Research Group

Dept of Pharmaceutical Biosciences

Uppsala University

Sweden

2 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

Glucose-Insulin System The glucose homeostatis is tightly regulated

3 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

Glucose-Insulin System The glucose homeostatis is tightly regulated

Insulin stimulates glucose uptake from blood +

4 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

Diabetes Mellitus Mechanisms of diabetes

Insulin stimulates glucose uptake from blood +

Type 2 Type 1

5 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

Diabetes Mellitus Reasons to treat hyperglycemia

Chronic disease with high glucose in blood (hyperglycemia).

Acute hyperglycemia

• Extreme thirst, frequent urination, weight loss, cardiac arrhythmia, ketoacidosis (related to lack of insulin)

Chronic hyperglycemia

• Microvascular complications e.g. Retinopathy, Neuropathy, Nephropathy

• Macrovascular complications e.g. Cardiovascular disease

6 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

Diabetes Mellitus Monitoring glucose

• Fasting glucose – FPG • Sensitive to length of fasting

• Postprandial glucose – PPG • Sensitive to size of meal

• HbA1c • Glycation of haemoglobin

• Average glucose over 2-3 months

Sensitive to stress, circadian rhythms, etc.

7 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

Diabetes Mellitus Progression towards type 2 diabetes

8 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

Population tested on

Biomarkers

Anti-Diabetes Drug Development Biomarkers and populations used in anti-diabetic studies

Glucose & Insulin HbA1c

Cardiovascular

Animal model, e.g. ZFD rats Healthy

volunteers (HV)

Patients Metformin

treated patients

Phase III/IV Phase I/II Preclinical Lead

Discovery

9 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

Anti-Diabetes Drug Development Modelling and simulation can aid in informing decisions

• Quantification of drug effects

• Study design optimisation

• Translation from animal studies to human

• Predictions of long-term gain

• Dose response

• Bridging from phase 1 studies to phase 2 studies

10 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

Semi-mechanistic model Mechanistic models used in anti-diabetes drug development

• Integrated Glucose – Insulin (IGI) model

• Beta-cell mass – Insulin – Glucose (BIG) model

• FPG-HbA1c model

• Integrated Glucose – RBC – HbA1c (IGRH) model

11 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

Integrated Glucose-Insulin Model* The IGI model describes the biomarker glucose-insulin

Model development based on simultaneous analysis of: • Glucose and insulin time-course data

• Patient and healthy volunteer data

• Various short-term provocation studies: IV glucose tolerance test (IVGTT), oral glucose tolerance test (OGTT), meal test (MTT) and a clamp study

*Silber HE, et al. J Clin Pharmacol. 2007; Jauslin PM, et al. J Clin Pharmacol 2007; Silber HE, et al. J Clin Pharmacol 2010; Jauslin PM, et al. J Clin Pharmacol 2011

12 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

IGI Model Differences between healthy volunteers (HV) and type 2 diabetics

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↓

↓

↓

↓

↓

IGI Model Differences between healthy volunteers (HV) and type 2 diabetics

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IGI Model Visual Predictive Check of differences between HV and T2DM

Time (min)

Glu

co

se c

on

ce

ntr

atio

n (

mg

/dl)

0 50 100 150 200 250 300

10

020

030

040

050

0

Time (min)

Insulin

co

nce

ntr

ation

(m

U/l)

0 50 100 150 200 250 300

050

10

015

020

025

030

0

Time (min)

Glu

co

se c

on

ce

ntr

atio

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mg

/dl)

0 50 100 150 200 250

10

020

030

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060

0

Time (min)

Insulin

(m

U/l)

0 50 100 150 200 250

020

040

060

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0

Hea

lth

y vo

lun

teer

s D

iab

etic

pat

ien

ts

Glucose Insulin

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↑ Insulin secretion

↑ Insulin-dependent elimination

Glucose absorption

IGI Model Differences between IVGTT and OGTT

↓

16 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

IGI Model Incretin effect

Experiment* Simulation

* Nauck M, et al. Diabetologia. 1986

OGTT Isoglycemic glucose infusion (IIGI)

Glucose

Insulin

17 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

Time (min)

Glu

co

se

co

nce

ntr

atio

n (

mg

/dl)

0 50 100 150 200 250

05

01

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Time (min)

Insu

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mU

/l)

0 50 100 150 200 250

15

10

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50

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Time (min)

Glu

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se

co

nce

ntr

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mg

/dl)

0 50 100 150 200 250

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02

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30

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06

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Time (min)

Insu

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mU

/l)

0 50 100 150 200 250

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12

0

Hea

lth

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s D

iab

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Glucose Insulin

IGI Model Visual Predictive Check of OGTT

18 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

IGI Model Circadian rhythm from 24 hours study

Glu

cose

In

sulin

In

sulin

sec

r.

Suppression function

Model prediction with suppression function

Model prediction without suppression function

19 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

IGI Model Visual Predictive Check of 24 hours profile with meal tolerance test

20 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

IGI Model Decision supported by the IGI model

• Quantification of drug effects

• Study design optimisation

• Translation from animal studies to human

• Predictions of long-term gain

• Dose reponse

• Bridging from phase 1 studies to phase 2 studies

21 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

IGI Model Quantifying drug effect of a GlucoKinase Activator and Glibenclamide

Insulin stimulates glucose uptake from blood +

GKA

Glibenclamide

+ _

+

22 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

IGI Model Study design of drug effect assessment data

Study design GKA*

• OGTT

• 15 Patients

• K-PD model for GKA (doses 25, 100 mg)

Study design Glibenclamide**

• MTT

• 8 Healthy Volunteers

• PK model with IV glibenclamide and 2 active metabolites. Oral glibenclamide

* Jauslin PM et al. J Clin Pharmacol 2012; ** Choy S et al. J PKPD 2012

23 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

IGI Model Quantification of drug effect and mechanism of action

24 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

IGI Model GKA: main effect - insulin secretion, minor - glucose production

25 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

IGI Model Visual predictive check of GKA effect (dose 100 mg)

TIME [min]

Co

nc

en

tra

tio

n [

mg

/dL

]

0 100 200 300 400

100

200

300

400

Glucose GKA Dose = 0 mg

TIME [min]

Co

nc

en

tra

tio

n [

mU

/L]

0 100 200 300 400

05

01

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150

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Insulin GKA Dose = 0 mg

TIME [min]

Co

nc

en

tra

tio

n [

mg

/dL

]

0 100 200 300 400

100

200

300

400

Glucose GKA Dose = 100 mg

TIME [min]

Co

nc

en

tra

tio

n [

mU

/L]

0 100 200 300 400

05

01

00

150

200

250

Insulin GKA Dose = 100 mg

26 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

IGI Model Glibenclamide: effect of parent and metabolites- insulin secretion

27 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

IGI Model Glibenclamide: effect of parent and metabolites- insulin secretion

Change in ΔOFV compared to base model (no drug)

28 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

IGI Model Visual predictive check for glibenclamide w external validation

29 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

IGI Model Design optimisation – what can we optimize on?

0 50 100 150 2000

50

100

150

200

250

300

350

400

450

IVGTT

time (min)

mg

/DL

Glucose

Insulin

Hot Glucose

Start time of infusion

Stop time of infusion

Infusion length

Insulin dose Glucose dose

Sample times

* Silber HE et al. J PKPD 2009

30 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

IGI Model Translation from healthy volunteer to rat*

* Alskär O et al. PAGE 2012

Allometrically scale all CL, V and k of the IGI model • IVGTT in healthy SD rats • Investigate mechanism of action for Exendin-4

EX-4

31 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

IGI Model Rat IVGTT can be scaled from human IVGTT … and vice versa?

Only parameter re-estimated First phase insulin amount

32 Maria Kjellsson The Pharmacometrics Research Group, Uppsala University

Beta-cell mass – Insulin – Glucose model* Describes relationship of glucose and insulin on beta cell mass

Model developed based on model by Topp**: • Changes is ratio between glucose and insulin informs about beta

cell mass

• Model by Topp

• Healthy volunteers

• Literature values

• For longer term assessment of drug effect on beta cell mass

*Ribbing J, et al. J Clin Pharmacol 2010 **Topp B, et al. J Theor Biol 2000